Effect of co-administration of varenicline and antidepressants on extracellular monoamine concentrations in rat prefrontal cortex

Since a substantial proportion of smokers have comorbid mood disorders, the smoking cessation aid varenicline might occasionally be prescribed to patients who are simultaneously treated with antidepressants. Given that varenicline is a selective nicotinic acetylcholine receptor partial agonist and not a substrate or inhibitor of drug metabolizing enzymes, pharmacokinetic interactions with various classes of antidepressants are highly unlikely. It is, however, conceivable that varenicline may have a pharmacodynamic effect on antidepressant-evoked increases in central monoamine release. Interactions resulting in excessive transmitter release could cause adverse events such as serotonin syndrome, while attenuation of monoamine release could impact the clinical efficacy of antidepressants. To investigate this we examined whether varenicline administration modulates the effects of the selective serotonin reuptake inhibitor sertraline and the monoamine oxidase inhibitor clorgyline, given alone and combined, on extracellular concentrations of the monoamines serotonin, dopamine, and norepinephrine in rat brain by microdialysis. Given the important role attributed to cortical monoamine release in serotonin syndrome as well as antidepressant activity, the effects on extracellular monoamine concentrations were measured in the medial prefrontal cortex. Responses to maximally effective doses of sertraline or clorgyline and of sertraline plus clorgyline were the same in the absence as in the presence of a relatively high dose of varenicline, which by itself had no significant effect on cortical monoamine release. This is consistent with the binding profile of varenicline that has insufficient affinity for receptors, enzymes, or transporters to inhibit or potentiate the pharmacologic effects of antidepressants. Since varenicline neither diminished nor potentiated sertraline- or clorgyline-induced increases in neurotransmitter levels, combining varenicline with serotonergic antidepressants is unlikely to cause excessive serotonin release or to attenuate antidepressant efficacy via effects on cortical serotonin, dopamine or norepinephrine release.     

Monitoring diabetes in patients with and without rheumatoid arthritis: a Medicare study

Introduction

Diabetes mellitus is a key predictor of mortality in rheumatoid arthritis (RA) patients. Both RA and diabetes increase the risk of cardiovascular disease (CVD), yet understanding of how comorbid RA impacts the receipt of guideline-based diabetes care is limited. The purpose of this study was to examine how the presence of RA affected hemoglobin A1C (A1c) and lipid measurement in older adults with diabetes.

Methods

Using a retrospective cohort approach, we identified beneficiaries ≥65 years old with diabetes from a 5% random national sample of 2004 to 2005 Medicare patients (N = 256,331), then examined whether these patients had comorbid RA and whether they received guideline recommended A1c and lipid testing in 2006. Multivariate logistic regression was used to examine the effect of RA on receiving guideline recommended testing, adjusting for baseline sociodemographics, comorbidities and health care utilization.

Results

Two percent of diabetes patients had comorbid RA (N = 5,572). Diabetes patients with comorbid RA were more likely than those without RA to have baseline cardiovascular disease (such as 17% more congestive heart failure), diabetes-related complications including kidney disease (19% higher), lower extremity ulcers (77% higher) and peripheral vascular disease (32% higher). In adjusted models, diabetes patients with RA were less likely to receive recommended A1c testing (odds ratio (OR) 0.84, CI 0.80 to 0.89) than those without RA, but were slightly more likely to receive lipid testing (OR 1.08, CI 1.01 to 1.16).

Conclusions

In older adults with diabetes, the presence of comorbid RA predicted lower rates of A1c testing but slightly improved lipid testing. Future research should examine strategies to improve A1c testing in patients with diabetes and RA, in light of increased CVD and microvascular risks in patients with both conditions.     

How do membrane proteins sense water stress?

Maintenance of cell turgor is a prerequisite for almost any form of life as it provides a mechanical force for the expansion of the cell envelope. As changes in extracellular osmolality will have similar physicochemical effects on cells from all biological kingdoms, the responses to osmotic stress may be alike in all organisms. The primary response of bacteria to osmotic upshifts involves the activation of transporters, to effect the rapid accumulation of osmoprotectants, and sensor kinases, to increase the transport and/or biosynthetic capacity for these solutes. Upon osmotic downshift, the excess of cytoplasmic solutes is released via mechanosensitive channel proteins. A number of breakthroughs in the last one or two years have led to tremendous advances in our understanding of the molecular mechanisms of osmosensing in bacteria. The possible mechanisms of osmosensing, and the actual evidence for a particular mechanism, are presented for well studied, osmoregulated transport systems, sensor kinases and mechanosensitive channel proteins. The emerging picture is that intracellular ionic solutes (or ionic strength) serve as a signal for the activation of the upshift-activated transporters and sensor kinases. For at least one system, there is strong evidence that the signal is transduced to the protein complex via alterations in the protein-lipid interactions rather than direct sensing of ion concentration or ionic strength by the proteins. The osmotic downshift-activated mechanosensitive channels, on the other hand, sense tension in the membrane but other factors such as hydration state of the protein may affect the equilibrium between open and closed states of the proteins.     

Creatine kinase isoenzyme activity during and after an ultra-distance (200 km) run

It is commonly assumed that creatine kinase (CK) activity in plasma is related to the state of an inflammatory response at 24-48 h, and also it has shown biphasic patterns after a marathon run. No information is available on CK isoenzymes after an ultra-marathon run. The purpose of the present study is to examine the CK isoenzymes after a 200 km ultra-marathon run and during the subsequent recovery. Blood samples were obtained during registration 1 2 h before the 200-km race and during the race at 100 km, 150 km and at the end of 200 km, as well as after a 24 h period of recovery. Thirty-two male ultra-distance runners participated in the study. Serum CPK showed a marked increase throughout the race and 24 h recovery period (p < 0.001). Serum CK during the race occurs mostly in the CK-MM isoform and only minutely in the CK-MB isoform and is unchanged in the CK-BB isoform. High-sensitivity C-reactive protein (hs-CRP), oestradiol, AST and ALT increased significantly from the pre-race value at 100 km and a further increase took place by the end of the 200 km run. The results of our study demonstrate a different release pattern of creatine kinase after an ultra-distance (200 km) run compared to the studies of marathon running and intense eccentric exercise, and changes in several biomarkers, indicative of muscle damage during the race, were much more pronounced during the latter half (100–200 km) of the race. However, the increases in plasma concentration of muscle enzymes may reflect not only structural damage, but also their rate of clearance.     

Motif kernel generated by genetic programming improves remote homology and fold detection

Background  

Protein remote homology detection is a central problem in computational biology. Most recent methods train support vector machines to discriminate between related and unrelated sequences and these studies have introduced several types of kernels. One successful approach is to base a kernel on shared occurrences of discrete sequence motifs. Still, many protein sequences fail to be classified correctly for a lack of a suitable set of motifs for these sequences.     

Lactococcus lactis uses MscL as its principal mechanosensitive channel

The functions of the mechanosensitive channels from Lactococcus lactis were determined by biochemical, physiological, and electrophysiological methods. Patch-clamp studies showed that the genes yncB and mscL encode MscS and MscL-like channels, respectively, when expressed in Escherichia coli or if the gene products were purified and reconstituted in proteoliposomes. However, unless yncB was expressed in trans, wild type membranes of L. lactis displayed only MscL activity. Membranes prepared from an mscL disruption mutant did not show any mechanosensitive channel activity, irrespective of whether the cells had been grown on low or high osmolarity medium. In osmotic downshift assays, wild type cells survived and retained 20% of the glycine betaine internalized under external high salt conditions. On the other hand, the mscL disruption mutant retained 40% of internalized glycine betaine and was significantly compromised in its survival upon osmotic downshifts. The data strongly suggest that L. lactis uses MscL as the main mechanosensitive solute release system to protect the cells under conditions of osmotic downshift.     

Lack of geographic variation in anonymous nuclear polymorphisms in the American oyster, Crassostrea virginica

Comparing geographic variation of noncoding nuclear DNA polymorphisms, which presumably are neutral to natural selection, with geographic variation of allozymes is potentially a good way to detect the effects of selection on allozyme polymorphisms. A previous study of four anonymous nuclear markers in the American oyster, Crassostrea virginica, found dramatic differences in allele frequency between the Gulf of Mexico and the Atlantic Ocean. In contrast, 14 allozyme polymorphisms were fairly uniform in frequency between the two areas. This led to the conclusion that all of the allozyme polymorphisms were kept uniform in frequency by balancing selection. To test the robustness of this pattern, six additional anonymous nuclear DNA polymorphisms were surveyed in oysters from Panacea, Fla, and Charleston, S.C. on the Gulf and Atlantic coasts, respectively. Unlike the previously studied DNA markers, the six DNA polymorphisms examined here show geographic variation that is not significantly greater than that of allozymes. The reason for the discrepancy between the two sets of DNA polymorphisms is unclear.      

Rituximab treatment in rheumatoid arthritis: how does it work?

Treatment with the chimerical monoclonal antibody rituximab results in CD20-directed B cell depletion. Although this depletion is almost complete in the peripheral blood of nearly all patients with rheumatoid arthritis, a proportion of patients does not exhibit a clinical response. The paper by Nakou and colleagues suggests that a decrease in CD19+CD27+ memory B cells in both peripheral blood and bone marrow precedes the clinical response to rituximab. This finding adds to the emerging evidence that lack of response to rituximab is associated with persistence of B lineage cells in specific body compartments.